Background: Osteoarthritis (OA) is a chronic progressive illness for which effective therapy is needed. It is the most common type of arthritis and results in burdensome disability and dependence among older Americans (1, 2). Knee OA preferentially affects and disables older women (3, 4). We hypothesize that the development of knee OA is not simply due to mechanical stress. We also hypothesize that skeletal muscle dysfunction contributes to knee OA-associated disability, and that inflammation plays a role in this process by enhancing damage and inhibiting repair. We have initiated three areas of investigation: epidemiological, basic, and clinical aspects of skeletal muscle as it relates to arthritis. Epidemiology: Obesity is a well-established risk factor for knee OA (5). Secondary analyses of longitudinal Baltimore Longitudinal Study of Aging (BLSA) data were performed to determine whether incident OA of the knee is associated with body fatness, independent of body weight and body mass index (6). Dual photon absorptiometry and anthropometric data were used to assess body composition and fatness, and conventional weight-bearing knee radiographs taken over a 10-year observation period to define OA status. Participants who developed knee OA had 4 kg higher fat mass (p=0.016), higher fat to lean mass ratio (60.97 versus 51.03; p <0.01), and higher percentage body fat (36.52 versus 32.43; p < 0.001) than those that did not develop knee OA. These observations persisted following adjustment for body mass index. These findings may explain why women are more likely to develop osteoarthritis of the knee. This may also suggest that the mechanisms by which excess weight contributes to OA development may extend beyond purely mechanical factors. We also conducted secondary analyses of the Women&#8217;s Health and Aging Study II data to seek clues to knee OA-associated disablement (7). The WHAS II study is a prospective study of 436 well-functioning women designed to elucidate the transition to clinically apparent physical disability. We analyzed data from 140 women with either knee and/or hip OA and 273 women without OA to determine if OA is associated with the development of mobility difficulty over 36 months. We found that women with OA were twice as likely to develop mobility difficulty over this time period, particularly with tasks that require strength and power. Additionally, BMI 25-29 increased risk of new mobility difficulty by 2.9 fold (95% CI 1.46, 5.92), and even higher with BMI >30 (relative risk 3.8; 95% CI 1.31, 11.05). Furthermore, body mass index > 25 increased the risk of developing knee or hip pain, while higher knee extensor strength reduced that risk. These data suggest that OA disables well-functioning older women, but also suggest that modifiable factors (weight excess, strength deficits) are important contributors to disablement and should be targeted for intervention along with pain management. Data from these two studies will be presented at the national meetings of the American College of Rheumatology, and the Osteoarthritis Research Society International this fall. We plan to supplement these analyses by conducting case-control studies to determine the utility of inflammatory and OA biomarkers in predicting OA development, progression, and disablement. Basic: A study designed to simultaneously examine the independent and combined effects of arthritis and hind limb unloading on skeletal muscle function in rodents was approved. Specifically, we have focused this study on characterizing the number and function of satellite cells (resident skeletal muscle precursors that are capable of differentiating into myoblasts and mature myocytes) in context of arthritis and hind limb unloading. We obtained skeletal muscle from pilot animals to determine whether old and young animals differ with regard to the presence of inflammatory cytokines and the satellite cell yield. We prepared skeletal muscle extracts from two 3 month and 1 22 month old animal, and performed assays for interleukin-1b, interleukin-6 and tumor necrosis factor-&#945;. We detected IL-1b (798.66 pg/ml), IL-6 (92.58 pg/ml), and TNF- alpha (153.45 pg/ml) in extracts obtained from young animals, but not detectable in extracts obtained from the old animal. With regard to SC populations, we have refined our tissue dissolution protocol and can isolate 3-7 x 10 6 cells from 17-24 grams of muscle from each animal, without significant differences between young and old animals (p> 0.05). We are in the process of determining whether these cells can be identified with antibodies directed to satellite cell markers. Thus far, we have found that these cells can be identified by antibody staining for c-met tyrosine kinase receptor by flow cytometry, and m-cadherin by immunohistochemistry. Upon completing the phenotypic characterization of these cells, we intend to determine whether these cells will proliferate and differentiate into skeletal muscle and in doing so acquire differentiation markers (desmin, myoD). Thus far, the cells acquired from 2 young rats have been subjected to propidium iodide cell cycle analyses and RNA extraction. In both cases cells were predominantly in the G0-G1 phase of the cell cycle, and produced minimal amounts of RNA (0.028 mg/ml from a single young rat). Clinical: We have obtained approval to initiate a patient-based study to test the above hypothesis. 44 knee OA patients and 44 age and gender-matched control subjects without OA will be recruited to undergo a battery of comprehensive physiologic tests that include an assessment of skeletal muscle strength, performance, an skeletal muscle biopsy. Recruitment will begin this fall. Muscle samples will be acquired from human subjects and animals and examined to determine whether arthritis is associated with inflammatory cytokine expression with regenerative potential, muscle quality, and function. The histochemical staining techniques that will be used to characterize fiber type and area, and to identify resident satellite cells in human and rat muscle samples have been developed. We have also begun to apply ELISA testing for several of the inflammatory cytokines mentioned above to rat muscle acquired from pilot animals. IMPLICATIONS This study will contribute to our understanding of the mechanisms by which knee OA disables older adults. If the data from these studies support our hypothesis that inflammatory processes contribute significantly to skeletal muscle dysfunction in the setting of knee OA, further studies will be designed to delineate the specific pathways involved with the intention of unveiling new therapeutic targets.